Apparatus and methods for diagnosing renal disorders

• US 8,481,324 B2
• Filed: 12/02/2009
• Issued: 07/09/2013
• Est. Priority Date: 12/04/2008
• Status: Active Grant

• Current Assignee: TECHNION RESEARCH AND DEVELOPMENT FOUNDATION, LTD.
• Original Assignee: TECHNION RESEARCH AND DEVELOPMENT FOUNDATION, LTD.
• Inventors: Haick, Hossam, Abassi, Zaid, Nakhoul, Farid
• Primary Examiner(s): Wallenhorst, Maureen
• Application Number:
  US13/131,345
• Publication Number:
  US 20110244584A1
• Time in Patent Office: 1,315 Days
• Field of Search: 436/63, 436/64, 436/71, 436/73, 436/80, 436/84, 436/96, 436/106, 436/111, 436/112, 436/128, 436/149, 436/151, 436/181, 422/83, 422/84, 422/88, 422/90, 422/91, 422/98, 506/7
• US Class Current: 436/63
• CPC Class Codes: B82Y 15/00 Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
• CPC Class Codes: G01N 2800/347 Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
• CPC Class Codes: G01N 33/0034 comprising neural networks or related mathematical techniques
• CPC Class Codes: G01N 33/497 of gaseous biological material, e.g. breath
• CPC Class Codes: Y10T 436/145555 Hetero-N
• CPC Class Codes: Y10T 436/172307 Cyanide or isocyanide
• CPC Class Codes: Y10T 436/173845 Amine and quaternary ammonium
• CPC Class Codes: Y10T 436/174614 Tertiary amine
• CPC Class Codes: Y10T 436/200833 Carbonyl, ether, aldehyde or ketone containing
• CPC Class Codes: Y10T 436/25875 Gaseous sample or with change of physical state

Abstract

The present invention provides a system containing an array of chemically sensitive sensors based on coated single walled carbon nanotubes, for measuring volatile organic compounds indicative of renal failure. Methods of breath analysis for diagnosing chronic, acute and end-stage renal failure are disclosed.

Claims

1. A method for diagnosing renal failure in a subject, the method comprising:

(a) providing a system comprising an apparatus comprising an array of chemically sensitive sensors of single walled carbon nanotubes coated with an organic coating, wherein the organic coating comprises polymers or oligomers that are modified with at least one polar functional group; and

a processing unit comprising a learning and pattern recognition analyzer wherein the learning and pattern recognition analyzer receives sensor signal output signals and compares them to stored data,

(b) exposing the sensor array of the apparatus to a breath sample to detect volatile organic compounds in the breath sample, and

(c) using a pattern recognition algorithm to determine the presence of the volatile organic compounds in the sample that are indicative of the renal failure in the subject, thereby providing a diagnosis of renal failure.

2. The method of claim 1, wherein the renal failure is acute renal failure, chronic renal failure, end stage renal failure, tubular interstitial disease, or glomerulonephritis;

or wherein the renal failure occurs as a result of renal cancer.

3. The method of claim 1, wherein the polymers are selected from the group consisting of nafion, polyethyleneimine, methylamine dehydrogenase, poly(aniline-boronic acid), amine-terminated poly(amido amine)dendrimers, poly(4-vinylpyridine), poly(ethylene oxide), polystyrene, poly(methyl vinyl ether-co-maleic anhydride), poly(ethylene-co-vinyl acetate), poly(ethylene glycol), poly(vinyl butyral), polycarbonate, poly(4-vinyl phenol), polycaprolactone, poly-(fluorostyrene), poly(styrene-co-isoprene), poly(maleic anhydride)-co-poly(methylvinyl ether), and combinations thereof;

or

wherein the polymers are crosslinked polymers selected from the group consisting of cross-reactive carboxylic acid substituted poly(thiophene), cross-linked dendrimerics of 1-[4-(4-dimethylamino-phenylazo)-3-[3,5-bis[3,5-bis[3,5-bis(3-butene-1-oxy)benzyloxy]benzyloxy]benzyloxy]phenyl]-2,2,2 trifluoroethanone and 1-[4-(4-dimethylaminophenylazo)-3-[3,5-bis[3,5-bis[3,5-bis(2-propene-1-oxy)benzyloxy]benzyloxy]benzyloxy]phenyl]-2,2,2 trifluoro-ethanone, cross-linked poly(p-phenyleneethynylene) containing osmium(II) complex and aldehyde groups, and combinations thereof;

or

wherein the oligomers are cyclodextrins selected from the group consisting of α

-cyclodextrin, β

-cyclodextrin, γ

-cyclodextrin, methyl-β

-cyclodextrin, 2,6-dibutyl-β

-cyclodextrin, hydroxypropyl-β

-cyclodextrin, 2,6-di-O-methyl-β

-cyclodextrin, permethylated α

-cyclodextrin-6^A-monoalcohol nitrate, dinitrophenyl substituted β

-cyclodextrin-based chiral stationary phases, β

- and γ

-cyclodextrins bearing 4-amino-7-nitrobenz-2-oxa-1,3-diazole functional groups, sulfated and carboxy-methylated β

-cyclodextrins, mono(6-cyclohexylamino-6-deoxy)-β

-cyclodextrin, mono-(6-benzyl-imino-6-deoxy)-β

-cyclodextrin, mono[6-(o-amino-phenyl)imino-6-deoxy]-β

-cyclodextrin, mono[6-(p-aminophenyl)imino-6-deoxy]-β

-cyclodextrin, mono[6-(α

-naphthyl)imino-6-deoxy]-β

-cyclodextrin, hexakis(6-O-benzoyl)-α

-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β

-cyclodextrin, hexakis(6-O-benzoyl-2,3-di-O-benzyl)-α

-cyclodextrin, hexakis(2,3-di-O-benzyl)-α

-cyclodextrin, 2-6-amino-β

-cyclodextrin, permethylated-β

-cyclodextrin, 2A,3A-Alloepithio-2A,3A-dideoxy-β

-cyclodextrin, and combinations thereof.

4. The method of claim 1, wherein the array of chemically sensitive sensors further comprises sensors of single walled carbon nanotubes coated with compounds selected from the group consisting of 2,5-bis(dimethylthiocarbamoyloxy)terephthalic acid diethyl ester, 2,5-bis(dimethyl-thiocarbamoyl-sulfanyl)terephthalic acid diethyl ester, 2,5-dimercaptoterephthalic acid, n-(3-trifluoroethanesulfonyloxypropyl)-anthraquinone-2-carboxamide, 3-methyl 4-(tetraethoxy)thiophene, 3-[n-succinimido(tetra-ethoxy)oxy]-4-methyl thiophene, quinacrine dihydrochloride dehydrate, lauric acid, quinacrine dihydrochloride, dihydrate phthalate, etracosanoic acid, 2,5,6,9,10-hexabromocyclododecane, and combinations thereof;

or

compounds selected from the group consisting of propyl gallate (C₁₀H₁₂O₅), anthracene (C₁₄H₁₀), tetracosanoic acid (C₂₄H₄₈O₂), tricosane (C₂₃H₄₈), 3-methyl-2-phenyl valeric acid (C₁₂H₁₆O₂), tris(hydroxymethyl)nitro-methane (C₄H₉NO₅), tetracosane (C₂₄H₅₀), dioctyl phthalate((C₂₄H₃₈O₄)), 1,2,5,6,9,10-hexabrormo-cyclododecane (C₁₂H₁₈Br₆), pentadecane (C₁₅H₃₂), and combinations thereof;

or

hexa-peri-hexabenzocoronene (HBC) derivatives selected from the group consisting of HBC-C_6,2, HBC-C_10,6, HBC-C_14,10, and HBC-C₁₂.

5. The method of claim 1, wherein the sensors are configured in a form selected from the group consisting of capacitive sensors, resistive sensors, impedance sensors, and field effect transistor sensors.

6. The method of claim 1 further comprising the step of collecting the sample into a breath collector prior to step (b), wherein the breath collector comprises at least one of a unit for concentrating breath analytes and a dehumidifying unit.

7. The method of claim 1, wherein the learning and pattern recognition analyzer comprises at least one algorithm selected from the group consisting of artificial neural network algorithms, principal component analysis (PCA), multi-layer perception (MLP), generalized regression neural network (GRNN), fuzzy inference systems (FIS), self-organizing map (SOM), radial bias function (RBF), genetic algorithms (GAS), neuro-fuzzy systems (NFS), adaptive resonance theory (ART), partial least squares (PLS), multiple linear regression (MLR), principal component regression (PCR), discriminant function analysis (DFA), linear discriminant analysis (LDA), cluster analysis, and nearest neighbor.

8. The method of claim 1, wherein the array of chemically sensitive sensors further comprises sensors of metal nanoparticles capped with an organic coating.

9. The method of claim 8, wherein the metal nanoparticles are selected from the group consisting of Au, Ag, Ni, Co, Pt, Pd, Cu, and Al nanoparticles.

10. The method of claim 8, wherein the organic coating of the metal nanoparticles comprises compounds selected from the group consisting of alkylthiols, arylthiols, alkylarylthiols, alkylthiolates, ω

-functionalized alkylthiolates, arenethiolates, (γ

-mercaptopropyl)tri-methyloxysilane, and combinations and derivatives thereof.

11. The method of claim 1, wherein the volatile organic compounds in the sample indicative of the renal failure in the subject are selected from the group consisting of dimethylamine, trimethylamine, isopalmitate, isopropyl palmitate, isothiocyanato-cyclohexane, 5-methyl-2-(1-methylethyl)-cyclohexanone, nonanal, and 6-nitro-2-picoline.